Ileal fibrosis in Crohn?s Disease (CD) represents a complication in over 30% of CD patients, and leads to surgery in nearly 75% of this population. While therapies exist to manage CD-related inflammation, no approved medication exists to prevent or manage fibrosis, with surgery left as the only option. Despite surgical removal of fibrotic strictures, they often recur, requiring repeated surgeries. Strategies to predict who is more likely to develop these complications, and identification of targets for therapeutic intervention is needed. Our long-term goal is to develop a screening process for CD patients that incorporates a patient?s polygenic risk score, gut microbiota profile, and metabolome to identify individuals at high risk for developing fibrotic disease (for newly diagnosed patients) and propensity for disease recurrence (in individuals who have undergone surgery for removal of strictures). In parallel, we hope to identify key microbiota strongly associated with fibrosis and define their mechanism of action, so that microbially-directed therapy may become a viable therapeutic option for these patients. Our objective in this proposal is to define the relationship between polygenic risk, the microbiome, and the intestinal and peri-intestinal environment contributing to the fibrotic sub-phenotype in ileal CD. The central hypothesis of this proposal is that CD patients who develop fibrotic disease and recurrent strictures represent a sub-phenotype characterized by a hyper-reactivity of ileal immune cells, and fibroblasts in surrounding mesenteric fat, to certain microbiota. We hypothesize that immune reactivity to these microbiota in both the ileum and mesenteric fat may be determined by an individual?s polygenic risk score. Our rationale is that the identification of mechanisms to predict development of fibrosis will offer new therapeutic opportunities. Our specific aims will test the following hypotheses: (Aim 1) genetic susceptibility to ileal fibrosis is mediated by an excessive immune response to creeping fat (CrF) microorganisms; (Aim 2) ileal fibroblasts express collagen matrix genes in the context of inflammation, is microbially-driven, and is related to propensity for recurrent strictures; and (Aim 3) microorganisms associated with CrF will increase penetrance, severity, and/or shorten time to disease in a model of spontaneous fibrosis. This contribution is significant because it will add new aspects to our understanding of CD fibrosis by studying the microbiome, mesenteric fat, and polygenic risk scores to help define this complicated phenotype. These insights have the potential to offer new targets and points of intervention before complications occur. This option currently does not exist. Furthermore, this study will provide the most comprehensive characterization to-date of creeping fat and help answer the mystery of why this phenomenon occurs. This contribution is innovative because no studies to-date have investigated ileal CD fibrosis taking into account the contribution of creeping fat to the fibrotic milieu. Insight into the peri-intestinal environment, combined with microbial targets, and an individual?s genotype represents a combination of analyses that is both new, clinically relevant, and ultimately, translatable into future patient care.